Abstract for TER90057

Codeine Administered to CD-1 Mice on Gestational Days 6 Through 15

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.

Codeine, a widely used narcotic analgesic, was evaluated for potential developmental toxicity in timed-pregnant CD-1 mice (28-38 confirmed pregnancies per group). COD (0, 75, 150 or 300 mg/kg, bid) in distilled water was administered by gavage (po) throughout major organogenesis [gestational days 6 through 15].

No notable maternal toxicity was observed at the lowest dose (75 mg/kg, bid). Among the animals exposed to 150 mg COD/kg. only 1 nonpregnant female died whereas, the pregnant females exhibited neither mortality and nor clinical signs of toxicity. A decreasing trend for corrected maternal weight gain was observed with a significant reduction at 300 mg/kg. Among the high-dose females, mortality reached 19% (7 of 37) and relative liver weight increased.

No evidence of embryo/fetal toxicity was observed at the lowest dose (75 mg/kg, bid). Intrauterine growth retardation proved to be the most sensitive indicator of embryo/fetal toxicity in this study. Average fetal body weight per litter was significantly reduced below vehicle controls. At 150 and 300 mg/kg, the cumulative index of intrauterine mortality (e.g., resorptions plus late fetal deaths expressed as a percentage of implants per litter) exhibited a doserelated increasing trend, due to a significant increase in resorptions in the 300 mg/kg group as compared to the vehicle control group. Among live litters, the number of live fetuses per litter and the percentage of male fetuses per litter did not differ across treatment groups. The incidence of major malformations was low (less than or equal to 1.16% malformed fetuses per litter) in all dose groups, and the average percent malformed fetuses per litter did not differ statistically across groups. The percent females malformed per litter exhibited a significant increasing trend, but no individual COD-treated group was above the vehicle control for this endpoint.

In summary, the lowest dose (75 mg/kg, bid) was a no observed effect level for all indices of maternal and embryo/fetal toxicity. Reduced fetal body weight was observed at 150 mg/kg, bid, in the absence of significant treatment-related toxicity among pregnant females. Relative to codeine use in a clinical context, 150 mg/kg, bid is 100 times higher than the estimated clinical intake per dose and 33 times higher than the estimated clinical intake per day (e.g., 1.5 mg/kg per dose and 9 mg/kg/day ). Codeine exposure during gestation failed to increase the incidence of major fetal malformations even at the highest dose (300 mg/kg, bid) which produced a significant increase in the percentage of resorptions per litter. The 300 mg/kg dose was also associated with a significant decrease in average fetal body weight per litter, and 19% mortality among pregnant females.